Alteration in the expression or function of one or more a2-adrenergic receptor (a2-AR) subtypes may be involved in the development and/or maintenance of salt-induced hypertension. This proposal seeks to dissect the roles of the a2A-AR and a2B-AR subtypes in blood pressure (BP) regulation. Our working hypothesis is that the a2A-AR and a2B-AR subtypes located in the centers of cardiovascular control of the brain have opposing effects on BP: The predominant presynaptic a2A-AR's exert a tonic sympathoinhibitory by potensive action and their pharmacologic stimulation further attenuates sympathetic activity, On the contrary, the a2B-ARs exert a hypertensive effect and their activation (e.g., by sodium overload) leads to an accentuated hyperadrenergic hypertensive response. We propose the following Specific Aims:1. To further clarify in mice the role of the a2A-AR and a2B-AR, each acting unopposed, in shaping the cardiovascular phenotype, by assessing the hemodynamic and hormonal profile as well as BP responses to salt loading, selective pharmacologic agents and renal artery clipping. 2. To dissect in rats the central and peripheral effects of the two a2-AR subtypes after temporarily inhibiting the generation of each subtype by targeting selected gene sequences with antisense oligonucleotides injected either stereotaxically in the lateral cerebral ventriclear or the brainstem, or systemically, while monitoring BP, catecholamines and pharmacologic responses. Genetic engineering and gene treatment will be used along with pharmacologic probes in order to differentiate responses to activation or inhibition of each a2-AR subtype. The ultimate goal of this research is to develop the means to prevent or treat certain types of hypertension by selectively altering the central a2B AR subtype without affecting other a2-AR-mediated functions, such as mental alertness, as occurs with current nonselective central sympatholytic agents.